The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Pathogenic organisms are, by definition, capable of causing disease in an infected host. For clinical use of such organisms, attenuated vaccine strains are often created which exhibit reduced or eliminated virulence, but which still retain sufficient viability to stimulate a desired immune response against the pathogen or heterologous antigen(s) of interest. Attenuated vector platforms have been demonstrated to elicit protective responses specific for encoded heterologous antigens in a number of experimental models, including infectious and malignant diseases.
Although most attenuated vaccine vectors are viral, bacterial vaccine vector platforms have been developed for both prophylactic and therapeutic applications. Attenuated strains of many otherwise pathogenic bacteria are now available and the ease of manipulation for generating recombinant strains provides a means for using bacteria as efficacious delivery vehicles for a number of foreign proteins such as antigens associated with infectious diseases and cancer. Live attenuated bacterial vaccine strains have been developed from, inter alia, Listeria, Escherichia, Salmonella, Shigella, Lactobacillus, and Yersinia species.
While such vaccine strains may exhibit reduced virulence, their safety, particularly in immune compromised individuals, remains a concern. One example of a strategy to further reduce the risk of bacterial vaccines is the so-called Killed But Metabolically Active (“KBMA”) approach. KBMA vaccine strains are constructed by abrogating the capacity for nucleotide excision repair through deletion of DNA repair genes such as uvrA and uvrB. The gene deletion renders the bacteria exquisitely sensitive to photochemical inactivation through the combined treatment of psoralens and UVA. Because of their inability to repair the psoralen-induced DNA cross-links formed, KBMA bacterial strains are unable to replicate and are thus functionally noninfectious. This characteristic provides an improved safety profile in comparison to live attenuated strains. The very limited number of cross-links, however, preserves their metabolic activity, including antigen expression, and thus their immune potential. Manufacturing of KBMA strains exhibiting consistent properties, however, may be difficult, as titration of the number of cross-links is dependent on a number of difficult to control variables.
There remains a need in the art to provide attenuated bacterial vaccine strains with advantageous safety profiles for use treatment or prevention of diseases having a risk-benefit profile not appropriate for live attenuated vaccines.